Breast cancer cells respond to both steroid hormones such as estrogen and polypeptides growth factors such as insulin-like growth factor-1 (IGF-I) . Because increased IGF-I activity correlates with tumor cell aggressiveness in vitro, and may correlate with tumor responsiveness in breast cancer patients, we have investigated whether signal transduction pathways downstream from the IGF-I receptor are activated in breast cancer cells. Activation of Akt, MAPK, and isoforms of protein kinase C was noted in multiple breast cancer cell lines. Activation of these pathways was exploited using pharmacologic inhibitors to increase programmed cell death (apoptosis). Experiments utilizing genetic approaches to abrogate kinase activity and to combine kinase inhibition with traditional forms of therapy and other inducers of apoptosis are underway. Exploitation of IGF-I stimulated signalling is a novel approach to promote breast cancer cell apoptosis and may eventually have therapeutic implications.